Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance

Azzimato, Valerio; Jager, Jennifer; Chen, Ping; Morgantini, Cecilia; Levi, Laura; Barreby, Emelie; Sulen, André; Oses, Carolina; Willerbrords, Joost; Xu, Connie; Li, Xidan; Shen, Joanne X.; Akbar, Naveed; Haag, Lars; Ellis, Ewa; Wålhen, Kerstin; Näslund, Erik; Thorell, Anders; Choudhury, Robin P.; Lauschke, Volker M.; Rydén, Mikael; Craige, Siobhan M.; Aouadi, Myriam

doi:10.1126/scitranslmed.aaw9709

Cited by 44 publications

(34 citation statements)

References 71 publications

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“…M1 and M2 in adipose tissues play an interactive role in the development of insulin resistance. For instance, during the development of obesity, adipose tissue macrophages could shift from the M2 polarized state to M1 state, which leads to chronic inflammation and insulin resistance [65].…”

Section: Inflammation and Oxidative Stress Cause Insulin Resistance Imentioning

confidence: 99%

The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

Eguchi

Lau

et al. 2020

IJMS

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Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxidative stress, and responds by increasing antioxidant transcription levels. Therefore, Nrf2 has emerged as a critical new target for combating insulin resistance and subsequently, obesity. However, the effects of Nrf2 on insulin resistance and obesity are controversial. This review focuses on the current state of research on the interplay of inflammation and oxidative stress in obesity, the role of the Nrf2 pathway in obesity and insulin resistance, and the potential use of Nrf2 activators for the treatment of insulin resistance.

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Section: Inflammation and Oxidative Stress Cause Insulin Resistance Imentioning

confidence: 99%

The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

Eguchi

Lau

et al. 2020

IJMS

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“…However, the presence of redox imbalance and lipid peroxidation is a common characteristic of NAFLD and NASH [26] and the involvement of adaptive immunity seems to be a key factor in NAFLD progression. Accordingly, recently Azzimato V. et al described that liver macrophages are proinflammatory in NASH, but not in NAFLD and obesity, although sings of oxidative stress are present in both conditions as NRF2 is downregulated [126].…”

Section: The Role Of Prrsmentioning

confidence: 99%

Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression

Dallio

Sangineto

Romeo

et al. 2021

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.

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“…Oxidative stress and the associated damage have been suggested to link obesity and liver disease. Recently, Azzimato and colleagues 156 showed that oxidative stress was triggered by obesity in mouse and human livers. In parallel, nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor regulating the antioxidant response, was reduced, leading to an impaired antioxidant response.…”

Section: Gene Expression Modificationmentioning

confidence: 99%

Macrophage reprogramming for therapy

et al. 2021

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Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting-edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage-targeted approaches in human disease.

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Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance

Cited by 44 publications

References 71 publications

The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression

Macrophage reprogramming for therapy

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